African American patients have a 2.0 fold greater rate of HCV infection than Caucasians and they are more likely to be infected with Genotype 1 virus which is inherently more resistant to IFN therapy. Recent studies indicate that sustained virologic response (SVR) with IFN therapy is less in African Americans than Caucasians although some of this reflects the greater rate of Genotype 1 infection. Nonetheless, the log drop in HCV RNA levels during IFN therapy is significantly less in African Americans. A recent study has shown that SVR is significantly improved in African American patients treated with IFN and Ribavirin and approached that seen in Genotype 1 infected Caucasians. Most preliminary results from other centers have not verified greatly improved SVR in African American patients. However, in most studies the percentage (5-10%) of African American patients enrolled was substantially less than Caucasians; and this occurred even though the population size of African American patients in the US and the number of patients infected would predict that African Americans should account for 20-25% of the HCV study population. This lower rate of study enrollment in the African American patients is not unique to HCV clinical trials and its cause is multi-factorial. However, the reported lack of response in African American patients is a growing detriment to enrollment especially since therapy is prolonged, expensive and fraught with side effects. Thus, means to predict non-SVR and SVR early in therapy would be very useful in treating patients who are unlikely to develop SVR. The lack of response of African American patients could result from differences in: compliance, body weight, gender, viral production and clearance rates, IFN effectiveness in blocking viral production, IFN pharmacokinetics, genomic differences in the virus and differences in humoral and cell mediated response. Some of these factors can be analyzed in the clinical studies while others will need to be addressed in the ancillary studies. The kinetics of HCV response to IFN has been recently described to undergo a biphasic response with the lsr phase being rapid, dose-dependent and accounting for a 0.5 to 2.0 log drop in RNA levels within 24 hours. This phase reflects the effectiveness of IFN in blocking viral production. A second slower phase of viral decline follows which is not IFN dose dependent, reflects the death of HCV infected liver cells and correlates with the serum half-life IFN. Its decline slope is an excellent predictor of SVR with IFN monotherapy or combination therapy. In preliminary results, we and others have shown that SVR may be even predicted as early as 24 hr of initiating IFN based on first phase kinetic parameters. Therefore, the first Specific Aim of this study is to assess using viral kinetic modeling principles the best and earliest predictor(s) of SVR. In preliminary studies, we have shown that African American patients treated with IFN alone have a blunted lsr phase viral decline but more importantly a significantly slower second phase viral decline. Based on preliminary findings that second phase decline correlates directly with IFN half-life and that SVR may be improved in African American patients treated with PEG-IFN, we would suggest that this multi-centered trial use PEG-IFN with Ribavirin in order to obtain optimum treatment results.